Treatment outcomes for chronic myelogenous leukemia (CML) have shown major improvements as a result of
the development of the tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib for the disease-specific
molecular target BCR-ABL1 tyrosine kinase (TK), but a cure of CML by BCR-ABL1 TKIs has been rarely achieved.
CML cells are protected from cytotoxic insults, including those by TKIs, through various collaborative BCR-ABL1-
mediated and -independent mechanisms, as well as cell-intrinsic and -extrinsic molecular mechanisms. These protective
mechanisms include overlapping cell signaling pathways for normal hematopoietic proliferation, modulation of molecules
associated with the BCL2 family protein-regulated programmed cell death pathway, autophagic cell protection capability,
bone marrow environment-mediated cell protective signaling, abnormally upregulated genetic instability and other BCRABL1-
independent kinase activities. To develop a more effective treatment strategy for a cure by means of total leukemic
cell killing, a thorough understanding of how CML cells survive and resist cytotoxic insults is essential. In this article, we
review current knowledge about multifaceted BCR-ABL1-related and -unrelated mechanisms for survival and death of
CML cells and present suggestions for the development of new therapeutic strategies for complete elimination of residual
CML cells during TKI treatment.